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Tumor Necrosis Factor Alpha Maintains Denervation-Induced Homeostatic Synaptic Plasticity of Mouse Dentate Granule Cells

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Tumor Necrosis Factor Alpha Maintains Denervation-Induced Homeostatic Synaptic Plasticity of Mouse Dentate Granule Cells ORIGINAL RESEARCH ARTICLE published: 18 December 2013 doi: 10.3389/fncel.2013.00257 Tumor necrosis factor alpha maintains denervation-induced homeostatic synaptic plasticity of mouse dentate granule cells Denise Becker, Nadine Zahn,Thomas Deller and Andreas Vlachos* Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt, Frankfurt, Germany Edited by: Neurons which lose part of their input respond with a compensatory increase in excitatory Arianna Maffei, State University of synaptic strength. This observation is of particular interest in the context of neurological New York Stony Brook, USA diseases, which are accompanied by the loss of neurons and subsequent denervation Reviewed by: of connected brain regions. However, while the cellular and molecular mechanisms of Carlos D. Aizenman, Brown University, USA pharmacologically induced homeostatic synaptic plasticity have been identified to a certain David Stellwagen, McGill University, degree, denervation-induced homeostatic synaptic plasticity remains not well understood. Canada Here, we employed the entorhinal denervation in vitro model to study the role of tumor Alanna Watt, McGill University, α Canada necrosis factor alpha (TNF ) on changes in excitatory synaptic strength of mouse dentate granule cells following partial deafferentation. Our experiments disclose that TNFα is *Correspondence: Andreas Vlachos, Institute of Clinical required for the maintenance of a compensatory increase in excitatory synaptic strength Neuroanatomy, Neuroscience Center, at 3–4 days post lesion (dpl), but not for the induction of synaptic scaling at 1–2 dpl. Goethe-University Frankfurt, Furthermore, laser capture microdissection combined with quantitative PCR demonstrates Theodor-Stern Kai 7, Frankfurt 60590, α Germany an increase in TNF -mRNA levels in the denervated zone, which is consistent with our e-mail: [email protected] previous finding on a local, i.e., layer-specific increase in excitatory synaptic strength at 3–4 dpl. Immunostainings for the glial fibrillary acidic protein and TNFα suggest that astrocytes are a source of TNFα in our experimental setting. We conclude that TNFα- signaling is a major regulatory system that aims at maintaining the homeostatic synaptic response of denervated neurons. Keywords: entorhinal cortex lesion, homeostatic synaptic scaling, astrocytes, brain injury, organotypic slice cultures INTRODUCTION TNFα affects synaptic strength (Beattie et al., 2002; Stellwagen Homeostatic synaptic plasticity is a slow adaptive mechanism et al., 2005; Leonoudakis et al., 2008; Santello et al., 2011; He et al., which allows neurons to adjust their synaptic strength to per- 2012; Pribiag and Stellwagen, 2013), its precise role in synaptic turbations in network activity. It aims at keeping the firing plasticity remains controversial. Recently experimental evidence rate of neurons within a dynamic range and is considered has been provided that TNFα may act as a permissive rather fundamental for the normal functioning of the central ner- than instructive factor (Steinmetz and Turrigiano,2010). Likewise, vous system. Hence, in response to a prolonged reduction its impact on synaptic plasticity under pathological conditions in network activity neurons increase (“scale up”) the strength remains not well understood (for a recent review on the role of of their excitatory synapses (Turrigiano, 2012; Vitureira et al., TNFα in synaptic plasticity see Santello and Volterra, 2012). 2012; Wang et al., 2012; Davis, 2013). Using entorhinal den- Here, we studied the role of TNFα in denervation-induced ervation in vitro we recently showed that homeostatic synaptic synaptic plasticity using mature (≥18 days in vitro; div) entorhino- strengthening of excitatory synapses is observed in denervated hippocampal slice cultures (Del Turco and Deller, 2007). In these neuronal networks (Vlachos et al., 2012a, 2013a,b). This obser- cultures the axonal projection from the entorhinal cortex (EC) to vation indicates that homeostatic synaptic responses could play the outer molecular layer (OML) can be transected by removing an important role in a broad range of neurological diseases, the EC from the culturing dish (e.g., Vlachos et al., 2013a). This which are accompanied by the loss of central neurons and sub- leads to the partial deafferentation of dentate granule cells in the sequent denervation of connected brain regions. However, the OML, without directly damaging the dentate gyrus (DG; Müller molecular pathways involved in the regulation of denervation- et al., 2010). Using pharmacological and genetic approaches we induced homeostatic synaptic plasticity remain incompletely provide experimental evidence that denervation-induced synap- understood. tic plasticity is divided into a TNFα-independent early phase One of the factors suggested to control homeostatic synaptic [1–2 days postlesion (dpl)] and a TNFα-dependent late phase scaling following prolonged blockade of sodium channels with (3–4 dpl). Astrocytes seem to be a major source of TNFα in our tetrodotoxin (TTX) or pharmacological inhibition of ionotropic experimental setting. These results suggest an important role for glutamate receptors, is the pro-inflammatory cytokine TNFα TNFα in maintaining synaptic scaling responses in denervated (Stellwagen and Malenka, 2006). While it has been shown that neuronal networks, which could be of relevance in the context of Frontiers in Cellular Neuroscience www.frontiersin.org December 2013 | Volume 7 | Article 257 | 1 “fncel-07-00257” — 2013/12/16 — 15:26 — page1—#1 Becker et al. TNFα and denervation-induced synaptic plasticity neurological diseases in which neuronal death and denervation Germany) while recording evoked excitatory postsynaptic currents occur. from individual granule cells (Figure 2A; c.f. Vlachos et al., 2012a). MATERIALS AND METHODS DRUG TREATMENTS PREPARATION OF SLICE CULTURES Denervated and non-denervated slice cultures were treated with Experimental procedures were performed in agreement with the recombinant TNFα (0.1 μg/ml; Sigma, Germany) for 1 or 2 days. German law on the use of laboratory animals and approved by the Soluble recombinant TNF-receptor 1 (sTNFR, 10 μg/ml, Catalog animal welfare officer of Goethe-University Frankfurt (Faculty of number: 425-R1-050, R&D systems, USA) was applied directly Medicine). Entorhino-hippocampal slice cultures were prepared after the lesion for up to 4 days (incubation medium replaced at postnatal day 4–5 as previously described (e.g., Becker et al., once with fresh sTNFR-containing medium at 2 days). 2012; Vlachos et al., 2013a). C57BL/6J and TNFα-deficient mice (and their wildtype littermates) of either sex were used (Pasparakis LASER CAPTURE MICRODISSECTION OF RE-SLICED CULTURES et al., 1996; Golan et al., 2004; obtained from Jackson Laborato- Slice cultures were washed with phosphate buffered saline (PBS; ries, USA). Slice cultures were allowed to mature for ≥18 div in 0.1 M, pH 7.4), shock frozen at −80◦C in tissue freezing medium ◦ humidified atmosphere with 5% CO2 at 35 C before experimental (Leica Microsystems, Germany), re-sliced into 10 μm thick slices assessment. on a cryostat (Leica CM 3050 S) and mounted on PET foil metal frames (Leica, Germany) as described previously (Vlachos et al., ENTORHINAL CORTEX LESION 2013b). Re-sliced cultures were fixed in ice-cold acetone for 1 min Slice cultures (18–25 div) were transected using a sterile scalpel and incubated with 0.1% toluidine blue (Merck, Germany) at blade (Figures 1A,B; e.g., Vlachos et al., 2012a, 2013a). To room temperature for 1 min, before rinsing in ultrapure water ensure complete and permanent separation of the EC from the (DNase/RNase free, Invitrogen, USA) and 70% ethanol. PET foil hippocampus, the EC was removed from the culturing dish. metal frames were mounted on a Leica DM 6000B laser capture microdissection (LMD) system (Leica Microsystems, Germany) PERFORANT PATH TRACING with the section facing downward (Burbach et al., 2003). After Anterograde tracing of the entorhino-hippocampal pathway with adjusting intensity, aperture, and cutting velocity, the pulsed ultra- biotinylated and rhodamine conjugated dextranamine Mini-Ruby violet laser beam was carefully directed along the borders of the (Figure 2A; Molecular Probes, USA) was performed as described respective hippocampal layers of interest using a 20× objective previously (Kluge et al., 1998; Prang et al., 2003; Vlachos et al., lens (Leica Laser Microdissection, Software Version 7.4.1.4853). 2012a). Tissue from the OML, the inner molecular layer (IML) and the WHOLE-CELL PATCH-CLAMP RECORDINGS granule cell layer (GCL) of the suprapyramidal blade of the DG Whole-cell voltage-clamp recordings and post hoc identification were collected. Microdissected tissue was transferred by gravity of recorded neurons were carried out as previously described into microcentrifuge tube caps placed underneath the sections, μ (Vlachos et al., 2012a). Age- and time-matched non-denervated filled with 50 l guanidine isothiocyanate (GITC)-containing cultures prepared from the same animal or littermate animals buffer (RLT Buffer, RNeasy Mini Kit, Qiagen, Germany) with served as controls. Non-denervated control (or untreated) cul- 1% ß-mercaptoethanol (AppliChem GmbH; Germany). Suc- tures were recorded alternating with the recordings of denervated cessful tissue collection was verified by visually inspecting the and/or treated cultures (c.f., Vlachos et al., 2012a). All record- content of the tube caps. All samples
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